Amino Acid Compounds

ABSTRACT

A method for increasing the bioabsorption of amino acids in a human or animal is disclosed. The method includes administering to the human or animal a pharmaceutically effective amount of an amino acid compound consisting essentially of a nitrate or nitrite of an amino acid selected from the group consisting of Arginine, Agmatine, Beta Alanine, Citrulline, Creatine, Glutamine, L-Histidine, Isoleucine, Leucine, Norvaline, Ornithine, and Valine.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation application of the earlier U.S.Utility patent application to Ronald Kramer, et. al. entitled “AminoAcid Compounds,” application Ser. No. 12/336,938, filed Dec. 17, 2008,now pending, which is a continuation application of the earlier U.S.Utility patent application to Ronald Kramer, et. al. entitled “AminoAcid Compounds,” application Ser. No. 11/950,273, filed Dec. 4, 2007,now U.S. Pat. No. 7,777,074, which application claims the benefit of thefiling date of U.S. Provisional Patent Application 60973229 entitled“Amino Acid Compounds” to Ronald Kramer, et. al., filed on Sep. 18,2007, the disclosures of all of which being hereby incorporated entirelyherein by reference.

BACKGROUND

1. Technical Field

Aspects of this document relate generally to amino acid compounds.

2. Background

It is desirable to design new amino acid compounds that have propertieslacking in conventional amino acids, conventional nitrates, andconventional nitrites.

SUMMARY

In one aspect, this document features a method for increasing thebioabsorption of amino acids in a human or animal is disclosed. Themethod includes administering to the human or animal a pharmaceuticallyeffective amount of an amino acid compound consisting essentially of anitrate or nitrite of an amino acid selected from the group consistingof Arginine, Agmatine, Beta Alanine, Citrulline, Creatine, Glutamine,L-Histidine, Isoleucine, Leucine, Norvaline, Ornithine, and Valine.

Implementations may comprise one or more of the following. The aminoacid compound may further comprise a pharmaceutically acceptableadditive, wherein the additive is one of a carrier, excipient, binder,colorant, flavoring agent, preservative, buffer, dilutant, andcombinations thereof. The amino acid compound may be in the form of acapsule, tablet, pill, liquid, liquid suspension, vapor, gas, powder,granulate or pulverulence.

The foregoing and other aspects, features, and advantages will beapparent to those artisans of ordinary skill in the art from theDESCRIPTION and DRAWINGS, and from the CLAIMS.

DESCRIPTION Overview

Compounds containing both a carboxyl group and an amino group aretypically known as Amino Acids. Amino Acids typically have the basicformula X-R, wherein X is:

Amino Acids typically differ from one another with respect to thestructure of the R group. It is the structure of the R group thattypically determines the individuality and character of each Amino Acid.

For example, the R group for the Amino Acid Arginine is:

Arginine is characterized as a nonessential Amino Acid. Specifically,Arginine can be independently manufactured by the human body, and doesnot need to be obtained directly through dietary intake. Arginine playsa significant role in healing, cell division, immune function, theelimination of ammonia from the body and the release of hormones.Arginine is presently used in the dietary supplement industry tosupplement Arginine production in the body. Arginine is also presentlyused in the dietary supplement industry to boost Human Growth Hormone(HGH) production, increase vasodilation, enhance blood circulation,increase oxygen flow to the muscles, and boost Nitric Oxide (NO)production. Various supplemental Arginine forms are available in theconsumer marketplace.

The vasodilating effect of ingested Arginine takes considerable time tomanifest since Arginine requires extensive metabolism to yield NitricOxide (NO). Additionally, considerable amounts of Arginine are requiredto produce a significant vasodilating effect, with common doses rangingfrom eight to twenty-four grams per day.

The R group for the Amino Acid Citrulline is:

Citrulline is an alpha-Amino Acid naturally occurring in the human body,and does not need to be obtained directly through dietary intake. Invivo, Citrulline is made from the Amino Acid Ornithine, along withcarbamoyl phosphate in one of the central reactions in the Urea Cycle.Citrulline is also produced during the metabolism of Arginine in thebody. Citrulline is presently used in the dietary supplement industry tosupplement Citrulline production in the body. By itself, Citrulline hasno vasodilating properties. Citrulline is also water insoluble, whichreduces its bioavailability and limits the forms in which Citrulline maybe effectively used.

The R group for the Amino Acid Creatine is:

Creatine is a nonessential Amino Acid and is also a nitrogenous organicacid. Creatine is independently manufactured by the human body, and doesnot need to be obtained directly through dietary intake. Creatine playsa significant role in providing muscles with energy. Creatine ispresently used in the dietary supplement industry to supplement Creatineproduction in the body. Creatine is also presently used in the dietarysupplement industry to increase muscle-mass gains, improve athleticperformance and strength. Creatine, by itself, has no vasodilatingproperties. Citrulline is also water insoluble, which reduces itsbioavailability and limits the forms in which Citrulline may beeffectively used.

The R group for the Amino Acid Glutamine is:

Glutamine is a nonessential Amino Acid. Glutamine is the most abundantnaturally occurring, non-essential amino acid in the human body and isfound circulating in the blood, as well as stored in the skeletalmuscles. Glutamine plays a significant role in protein synthesis, musclegrowth, and wound healing. Glutamine is presently used in the dietarysupplement industry to supplement Glutamine production in the body.Glutamine is also presently used in the dietary supplement industry tomaintain the body's Glutamine pool. Glutamine, by itself, has novasodilating properties. Glutamine is also water insoluble, whichreduces its bioavailability and limits the forms in which Glutamine maybe effectively used. Additionally, Glutamine inhibits Nitric Acid (NO)production through downregulation of eNOS synthase.

The R group for the Amino Acid Leucine is:

Leucine is an essential Amino Acid, meaning that Leucine is notsynthesized in vivo in animals. Accordingly, Leucine must be ingested,usually as a component of proteins consumed directly through dietaryintake. Leucine plays a significant role in muscle protein synthesis.Leucine can also inhibit protein degradation in skeletal muscle, as wellas in the liver. Leucine is presently used in the dietary supplementindustry to supplement dietary Leucine sources. Leucine is alsopresently used in the dietary supplement industry to promote anabolismand stimulate muscle protein synthesis. Leucine, by itself, has novasodilating properties. Leucine is also water insoluble, which reducesits bioavailability and limits the forms in which Leucine may beeffectively used.

The R group for the Amino Acid Norvaline is:

Norvaline is a nonessential Amino Acid. Specifically, Norvaline can beindependently manufactured by the human body, and does not need to beobtained directly through dietary intake. Norvaline is presently used inthe dietary supplement industry to supplement Norvaline production inthe body. Norvaline is also presently used in the dietary supplementindustry to inhibit the enzyme arginase and thus reduce the conversionof Arginine to urea. Norvaline, by itself, has no vasodilatingproperties, although it enhances the vasodilating properties ofArginine. Norvaline is also water insoluble, which reduces itsbioavailability and limits the forms in which Leucine may be effectivelyused.

The R group for the Amino Acid Ornithine is:

Ornithine is a non-essential Amino Acid. That is, Ornithine isindependently manufactured by the human body, and does not need to beobtained directly through dietary intake. Ornithine plays a significantrole in the synthesis of polyamines, specifically via the action ofOrnithine decarboxylase. Ornithine is presently used in the dietarysupplement industry to supplement dietary Ornithine sources. Ornithineis also presently used in the dietary supplement industry to enhance thevasodilating properties in a series of products commonly known as “NOBoosters.” Ornithine exerts its vasodilating effect only by in vivoconversion to Arginine and then by following the pathway that convertsArginine to Nitric Acid (NO). Many grams of Ornithine, and aconsiderable amount of time, are required in order to assert itsvasodilating effect.

The R group for the Amino Acid Histidine is:

Histidine is a naturally-occurring Amino Acid and is coded for in DNA.Relatively small shifts in cellular pH will change the electrical chargeof Histidine. For this reason, Histidine finds its way into considerableuse as a coordinating ligand in metalloproteins, and also as a catalyticsite in certain enzymes. Histidine is currently used in the dietarysupplement industry to support carnosine production. Histidine, byitself, has no vasodilating properties. Additionally, Histidine is verypoorly water soluble, a fact that limits its bioavailability andutility. Histidine is presently used in the dietary supplement industryin the forms of single administration Histidine and Histidine HCl.

The R group for the Amino Acid Beta Alanine is:

Beta Alanine is the only naturally-occurring Beta Amino Acid. A BetaAmino Acid is one in which the Amino group is located at the betaposition (i.e. two atoms away) from the Carboxyl group. Beta Alanine isformed in vivo through the degradation of dihydrouracil and carnosine.Beta Alanine is the rate-limiting precursor of carnosine. Therefore,carnosine levels are limited by the amount of available Beta Alanine.Beta Alanine, by itself, has no vasodilating properties. Additionally,Beat Alanine is poorly water soluble, which limits its bioavailabilityand utility. Beta Alanine is presently used in the dietary supplementindustry to support carnosine production.

The chemical structure of Agmatine is:

Agmatine is the decarboxylation product of the Amino Acid Arginine andis an intermediate in polyamine biosynthesis. Agmatine is synthesized inthe brain and stored in synaptic vesicles in regionally selectiveneurons. Agmatine is released by depolarization and is inactivated byagmatinase. Agmatine binds to alpha2-adrenoceptors and imidazolinebinding sites. Agmatine likewise blocks N-methyl-D-aspartic acid (NMDA)receptor channels and other ligand-gated cationic channels.Additionally, agmatine inhibits nitric oxide synthase, and induces therelease of some peptide hormones. Agmatine modulates nitric oxidethrough various mechanisms. Agmatine stimulates some types of nitricoxide synthase (NOS) while inhibiting others. Agmatine inhibits NitricOxide production by inhibiting NOS. Agmatine is presently used in thedietary supplement industry in the forms of single administrationAgmatine and Agmatine Sulfate.

Nitrates are a class of compounds that are salts of Nitric Acid (HNO₃)and at least comprise one Nitrogen atoms and three Oxygen atoms (NO₃).

Nitrites are a class of compounds that are salts of Nitrous Acid (HNO₂)and at least comprise one Nitrogen atom and two Oxygen atoms (NO₂).

Nitrates and Nitrites are commercially available in various preparationsand are used in various commercial applications. In the case ofingestion by humans, Nitrate (NO₃) is typically reduced to Nitrite (NO₂)in the epithelial cells of blood vessels. In vivo, Nitrite (NO₂) reactswith a thiol donor, principally glutathione, to yield Nitric Oxide (NO).

TERMINOLOGY AND DEFINITIONS

In describing implementations of an Amino Acid Compound, the followingterminology will be used in accordance with the definitions andexplanations set out below. Notwithstanding, other terminology,definitions, and explanations may be found throughout this document, aswell.

As used herein, “Amino Acid” is a term used in its broadest sense andmay refer to an Amino Acid in its many different chemical formsincluding a single administration Amino Acid, its physiologically activesalts or esters, its combinations with its various salts, itstautomeric, polymeric and/or isomeric forms, its analog forms, itsderivative forms, and/or its decarboxylation products. Amino Acidscomprise, by way of non-limiting example: Agmatine, Beta Alanine,Arginine, Asparagine, Aspartic Acid, Cysteine, Glutamine, Glutamic Acid,Glycine, Histidine, Isoleucine, Leucine, Lysine, Methionine, PhenylBetaAlanine, Proline, Serine, Threonine, Tryptophan, Tyrosine, and Valine.

As used herein, “Compound” is a term used in its broadest sense and mayrefer to an Amino Acid in combination with one of a Nitrate and aNitrite.

As used herein, “Nitrate” is a term used in its broadest sense and mayrefer to an Nitrate in its many different chemical forms including asalt of Nitric Acid, a single administration Nitrate, itsphysiologically active salts or esters, its combinations with itsvarious salts, its tautomeric, polymeric and/or isomeric forms, itsanalog forms, and/or its derivative forms. Nitrate comprises, by way ofnon-limiting example, many different chemical forms including dinitrateand trinitrate. Nitrates may be salts, or mixed salts, of Nitric Acidand comprise one Nitrogen atom and three Oxygen atoms. For the exemplarypurposes of this disclosure, Nitrate may comprise salts of Nitrate suchas sodium nitrate, potassium nitrate, barium nitrate, calcium nitrate,and the like. For the exemplary purposes of this disclosure, Nitrate mayinclude mixed salts of Nitrate such as nitrate orotate, and the like.Additionally, for the exemplary purposes of this disclosure, Nitrate maycomprise nitrate esters such as nitroglycerine, and the like.

As used herein, “Nitrite” is a term used in its broadest sense and mayrefer to an Nitrite in its many different chemical forms including asalt of Nitrous Acid, a single administration Nitrite, itsphysiologically active salts or esters, its combinations with itsvarious salts, its tautomeric, polymeric and/or isomeric forms, itsanalog forms, and its derivative forms. Nitrite comprises, by way ofnon-limiting example, many different chemical forms including dinitriteand trinitrite. Nitrites may be salts, or mixed salts, of Nitrous Acidand comprise one Nitrogen atom and two Oxygen atoms. For the exemplarypurposes of this disclosure, Nitrite may comprise salts of Nitrite suchas sodium nitrite, potassium nitrite, barium nitrite, calcium nitrite,and the like. For the exemplary purposes of this disclosure, Nitrite maycomprise mixed salts of Nitrite such as nitrite orotate, and the like.Additionally, for the exemplary purposes of this disclosure, Nitrite maycomprise nitrite esters such as amyl nitrite, and the like.

As used herein, “pharmaceutically acceptable additive” or “additive” areterms used in their broadest sense. Particular implementations of thecompositions described in this document may also comprise an additive(e.g. one of a solubilizer, an enzyme inhibiting agent, ananticoagulant, an antifoaming agent, an antioxidant, a coloring agent, acoolant, a cryoprotectant, a hydrogen bonding agent; a flavoring agent,a plasticizer, a preservative, a sweetener, a thickener, andcombinations thereof) and/or a carrier (e.g. one of an excipient, alubricant, a binder, a disintegrator, a diluent, an extender, a solvent,a suspending agent, a dissolution aid, an isotonization agent, abuffering agent, a soothing agent, an amphipathic lipid delivery system,and combinations thereof). These additives may be solids or liquids, andthe type of additive may be generally chosen based on the type ofadministration being used. Those of ordinary skill in the art will beable to readily select suitable pharmaceutically effective additivesfrom the disclosure in this document. In particular implementations,pharmaceutically acceptable additives may include, by non-limitingexample, calcium phosphate, cellulose, stearic acid, croscarmelosecellulose, magnesium stearate, and silicon dioxide.

As used in this document, “pharmaceutically effective” is a phrase usedin its broadest sense, including, by non-limiting example, effective ina clinical trial, for a specific patient, or only placebo-effective.

As used in this document, “Pharmaceutically acceptable” is a phrase usedin its broadest sense and may describe ingredients of a pharmaceuticalcomposition that meet Food and Drug Administration (FDA) standards,United States Pharmacopeial Standards (USP), US Department ofAgriculture (USDA) standards for food-grade materials, commonly acceptedstandards of the nutritional supplement industry, industry standards,botanical standards, or standards established by any individual. Thesestandards may delineate acceptable ranges of aspects of ingredients of apharmaceutical composition such as edibility, toxicity, pharmacologicaleffect, or any other aspect of a chemical, composition, or preparationused in implementations of a pharmaceutical composition.

Compounds/Components

A first implementation is an Arginine compound of the formula:

wherein;R is the Arginine group identified and defined above;X is the Amino Acid base identified and defined above; andY is selected from the group consisting of a Nitrate and a Nitrite.

Applicants have cost-effectively synthesized Arginine Nitrate bycombining nitric acid and Arginine, mixing with water, and leaving tocrystallize. Further nitratization can take place, yielding ArginineDinitrate or Arginine Trinitrate. An alternative implementation maycomprise using Nitrous Acid (HNO₂) instead of Nitric Acid (HNO₃), thusyielding Arginine Nitrite. Arginine Nitrite has the same effects asArginine Nitrate, the only difference being that it requires one lessstep to yield Nitric Oxide (NO—). Mixed salts may also be used, such asin the non-limiting example of Arginine Nitrate-Orotate.

A second implementation is a Citrulline compound of the formula:

wherein;R is the Citrulline group identified and defined above;X is the Amino Acid base identified and defined above; andY is selected from the group consisting of a Nitrate and a Nitrite.

Applicants have cost-effectively synthesized Citrulline Nitrate bycombining nitric acid and Citrulline, mixing with water, and leaving tocrystallize. Further nitratization can take place, yielding CitrullineDinitrate or Citrulline Trinitrate. An alternative implementation maycomprise using Nitrous Acid (HNO₂) instead of Nitric Acid (HNO₃), thusyielding Citrulline Nitrite. Citrulline Nitrite has the same effects asCitrulline Nitrate, the only difference being that it requires one lessstep to yield Nitric Oxide (NO—). Mixed salts may also be used, such asin the non-limiting example of Citrulline Nitrate-Orotate.

A third implementation is a Creatine compound of the formula:

wherein;R is the Creatine group identified and defined above;X is the Amino Acid base identified and defined above; andY is selected from the group consisting of a Nitrate and a Nitrite.

Applicants have cost-effectively synthesized Creatine Nitrate bycombining nitric acid and Creatine, mixing with water, and leaving tocrystallize. Further nitratization can take place, yielding CreatineDinitrate or Creatine Trinitrate. An alternative implementation maycomprise using Nitrous Acid (HNO₂) instead of Nitric Acid (HNO₃), thusyielding Creatine Nitrite. Creatine Nitrite has the same effects asCreatine Nitrate, the only difference being that it requires one lessstep to yield Nitric Oxide (NO—). Mixed salts may also be used, such asin the non-limiting example of Creatine Nitrate-Orotate.

A fourth implementation is a Glutamine compound of the formula:

wherein;R is the Glutamine group identified and defined above;X is the Amino Acid base identified and defined above; andY is selected from the group consisting of a Nitrate and a Nitrite.

Applicants have cost-effectively synthesized Glutamine Nitrate bycombining nitric acid and Glutamine, mixing with water, and leaving tocrystallize. Further nitratization can take place, yielding GlutamineDinitrate or Glutamine Trinitrate. An alternative implementationcomprises using Nitrous Acid (HNO₂) instead of Nitric Acid (HNO₃), thusyielding Glutamine Nitrite. Glutamine Nitrite has the same effects asGlutamine Nitrate, the only difference being that it requires one lessstep to yield Nitric Oxide (NO—). Mixed salts may also be used, such asin the non-limiting example of Glutamine Nitrate-Orotate.

A fifth implementation is a Leucine compound of the formula:

wherein;R is the Leucine group identified and defined above;X is the Amino Acid base identified and defined above; andY is selected from the group consisting of a Nitrate and a Nitrite.

Applicants have cost-effectively synthesized Leucine Nitrate bycombining nitric acid and Leucine, mixing with water, and leaving tocrystallize. Further nitratization can take place, yielding LeucineDinitrate or Leucine Trinitrate. An alternative implementation comprisessubstituting the Amino Acids Valine or Isoleucine for Leucine. Anotheralternative implementation comprises substituting Nitrous Acid (HNO₂)for Nitric Acid (HNO₃), thus yielding Leucine Nitrite. Leucine Nitritehas the same effects as Leucine Nitrate, the only difference being thatit requires one less step to yield Nitric Oxide (NO—). Mixed salts mayalso be used, such as in the non-limiting example of LeucineNitrate-Orotate.

A sixth implementation is a Norvaline compound of the formula:

wherein;R is the Norvaline group identified and defined above;X is the Amino Acid base identified and defined above; andY is selected from the group consisting of a Nitrate and a Nitrite.

Applicants have cost-effectively synthesized Norvaline Nitrate bycombining nitric acid and Norvaline, mixing with water, and leaving tocrystallize. Further nitratization can take place, yielding NorvalineDinitrate or Norvaline Trinitrate. An alternative implementationcomprises substituting Nitrous Acid (HNO₂) for Nitric Acid (HNO₃), thusyielding Norvaline Nitrite. Norvaline Nitrite has the same effects asNorvaline Nitrate, the only difference being that it requires one lessstep to yield Nitric Oxide (NO—). Mixed salts may also be used, such asin the non-limiting example of Norvaline Nitrate-Orotate.

A seventh implementation is an Ornithine compound of the formula:

wherein;R is the Ornithine group identified and defined above;X is the Amino Acid base identified and defined above; andY is selected from the group consisting of a Nitrate and a Nitrite.

Applicants have cost-effectively synthesized Ornithine Nitrate bycombining nitric acid and Ornithine, mixing with water, and leaving tocrystallize. Further nitratization can take place, yielding OrnithineDinitrate or Ornithine Trinitrate. An alternative implementationcomprises using Nitrous Acid (HNO₂) instead of Nitric Acid (HNO₃), thusyielding Ornithine Nitrite. Ornithine Nitrite has the same effects asOrnithine Nitrate, the only difference being that it requires one lessstep to yield Nitric Oxide (NO—). Mixed salts may also be used, such asin the non-limiting example of Ornithine Nitrate-Orotate.

An eighth implementation is a Histidine compound of the formula:

wherein;R is the Histidine group identified and defined above;X is the Amino Acid base identified and defined above; andY is selected from the group consisting of a Nitrate and a Nitrite.

Applicants have cost-effectively synthesized Histidine Nitrate bycombining nitric acid and Histidine, mixing with water, and leaving tocrystallize. Further nitratization can take place, yielding HistidineDinitrate or Histidine Trinitrate. An alternative implementationcomprises using Nitrous Acid (HNO₂) instead of Nitric Acid (HNO₃), thusyielding Histidine Nitrite. Histidine Nitrite has the same effects asHistidine Nitrate, the only difference being that it requires one lessstep to yield Nitric Oxide (NO—). Mixed salts may also be used, such asin the non-limiting example of Histidine Nitrate-Orotate.

A ninth implementation is a Beta Alanine compound of the formula:

wherein;R is the Beta Alanine group identified and defined above;X is the Amino Acid base identified and defined above; andY is selected from the group consisting of a Nitrate and a Nitrite.

Applicants have cost-effectively synthesized Beta Alanine Nitrate bycombining nitric acid and Beta Alanine, mixing with water, and leavingto crystallize. Further nitratization can take place, yielding BetaAlanine Dinitrate or Beta Alanine Trinitrate. An alternativeimplementation comprises using Nitrous Acid (HNO₂) instead of NitricAcid (HNO₃), thus yielding Beta Alanine Nitrite. Beta Alanine Nitritehas the same effects as Beta Alanine Nitrate, the only difference beingthat it requires one less step to yield Nitric Oxide (NO—). Mixed saltsmay also be used, such as in the non-limiting example of Beta AlanineNitrate-Orotate.

A tenth implementation is an Agmatine compound of the formula:

wherein;Y is selected from the group consisting of a Nitrate and a Nitrite.

Applicants have cost-effectively synthesized Agmatine Nitrate bycombining nitric acid and Agmatine, mixing with water, and leaving tocrystallize. Further nitratization can take place, yielding AgmatineDinitrate or Agmatine Trinitrate. An alternative implementationcomprises using Nitrous Acid (HNO₂) instead of Nitric Acid (HNO₃), thusyielding Agmatine Nitrite. Agmatine Nitrite has the same effects asAgmatine Nitrate, the only difference being that it requires one lessstep to yield Nitric Oxide (NO—). Mixed salts may also be used, such asin the non-limiting example of Agmatine Nitrate-Orotate.

Compositions and/or formulations may be administered in any form,including one of a capsule, a cachet, a pill, a tablet, a powder, agranule, a pellet, a bead, a particle, a troche, a lozenge, a pastille,a solution, an elixir, a syrup, a tincture, a suspension, an emulsion, amouthwash, a spray, a drop, an ointment, a cream, a gel, a paste, atransdermal patch, a suppository, a pessary, cream, a gel, a paste, afoam, and combinations thereof for example. Compositions and/orformulations may also include a acceptable additive (e.g. one of asolubilizer, an enzyme inhibiting agent, an anticoagulant, anantifoaming agent, an antioxidant, a coloring agent, a coolant, acryoprotectant, a hydrogen bonding agent, a flavoring agent, aplasticizer, a preservative, a sweetener, a thickener, and combinationsthereof) and/or a acceptable carrier (e.g. one of an excipient, alubricant, a binder, a disintegrator, a diluent, an extender, a solvent,a suspending agent, a dissolution aid, an isotonization agent, abuffering agent, a soothing agent, an amphipathic lipid delivery system,and combinations thereof).

Implementations of Amino Acid Nitrate and/or Nitrite Compounds may alsobe synthesized or created in a wide variety of manners, and may be madefrom a wide variety of materials. Those of ordinary skill in the artwill readily be able to select appropriate materials and methods tomanufacture and use the compounds disclosed herein.

Dosage Forms

Implementations of Amino Acid Compounds may conveniently be presented inunit dosage form. Unit dosage formulations may be those containing adaily dose or unit, a daily sub-dose, or an appropriate fractionthereof, of the administered components as described herein.

A dosage unit may include an Amino Acid Compound. In addition, a dosageunit may include an Amino Acid Compound admixed with a pharmaceuticallyacceptable additive(s), and/or any combination thereof.

The dosage units may be in a form suitable for administration bystandard routes. In general, the dosage units may be administered, bynon-limiting example, by the topical (including buccal and sublingual),transdermal, oral, rectal, ophthalmic (including intravitreal orintracameral), nasal, vaginal, and/or parenteral (includingsubcutaneous, intramuscular, intravenous, intradermal, intratracheal,and epidural) routes.

For the exemplary purposes of this disclosure, oral delivery may be aparticularly advantageous delivery route for administration to humansand animals of implementations of a pharmaceutical composition,optionally formulated with appropriate pharmaceutically acceptableadditives to facilitate administration.

Manufacture

Implementations of an Amino Acid Compound may be made using conventionalor other procedures. Accordingly, although there are a variety of methodimplementations for producing pharmaceutical compositions, for theexemplary purposes of this disclosure, a method implementation forproducing an Amino Acid Compound may comprise: measuring specificquantities of Amino Acid, Nitric or Nitrous Acid and water mixed in aspecific order the measured quantities of Amino Acid, Nitric or NitrousAcid and water, and any additional pharmaceutically acceptable additivesor inert ingredients, and then separating the pharmaceutical compositioninto discrete quantities for distribution and/or administration.

Measuring specific quantities of Amino Acid, Nitric or Nitrous Acid andwater, and pharmaceutically acceptable additives or inert ingredients,may involve any number of steps and implementing components, andmeasuring specific quantities of Amino Acid, Nitric or Nitrous Acid andwater, and pharmaceutically acceptable additives or inert ingredients,may be accomplished readily from this disclosure. For the exemplarypurposes of this disclosure, measuring specific quantities of AminoAcid, Nitric or Nitrous Acid and water, and pharmaceutically acceptableadditives or inert ingredients, may comprise using a scale, a solid orliquid dispensing apparatus, or other measurement device capable ofmeasuring solid mass or liquid volume to produce a desired quantity ofAmino Acid, Nitric or Nitrous Acid and water, and pharmaceuticallyacceptable ingredient.

It should be appreciated that any of the components of particularimplementations of an Amino Acid Compound may be used as suppliedcommercially, or may be preprocessed by, by non-limiting example, any ofthe methods and techniques of agglomeration, air suspension chilling,air suspension drying, balling, coacervation, comminution, compression,pelletization, cryopelletization, extrusion, granulation,homogenization, inclusion Compoundation, lyophilization, melting, mixed,molding, pan coating, solvent dehydration, sonication, spheronization,spray chilling, spray congealing, spray drying, or other processes knownin the art depending in part on the dosage form desired. The variouscomponents may also be pre-coated or encapsulated as known in the art.It will also be clear to one of ordinary skill in the art thatappropriate additives may also be introduced to the composition orduring the processes to facilitate the preparation of the dosage forms,depending on the need of the individual process.

Mixing the measured quantities of Amino Acid, Nitric or Nitrous Acid andwater, and pharmaceutically acceptable additives or inert ingredients,may involve any number of steps and implementing components, and may beaccomplished readily from this disclosure. For the exemplary purposes ofthis disclosure, mixed the measured quantities of Amino Acid, Nitric orNitrous Acid and water, and pharmaceutically acceptable additives orinert ingredients, may comprise combining the measured quantities of mAmino Acid, Nitric or Nitrous Acid and water, and pharmaceuticallyacceptable additives or inert ingredients, under the influence ofphysical, ultrasonic, or electrostatic forces to create a desired degreeof intermingling and/or chemical reaction of the Amino Acid, Nitric orNitrous Acid and water and any pharmaceutically acceptable ingredients.The mixed may be accomplished when the Amino Acid, Nitric or NitrousAcid and water and/or any pharmaceutically acceptable ingredients are ina solid, liquid, or semisolid state.

Separating the Amino Acid Compound into discrete quantities fordistribution may involve any number of steps and implementingcomponents, and separating the Amino Acid Compound into discretequantities for distribution may be accomplished readily from thisdisclosure. For the exemplary purposes of this disclosure, separatingthe Amino Acid Compound into discrete quantities for distribution mayinvolve utilizing a specific piece of equipment, for example, aconventional tablet forming apparatus to shape the formed compositioninto individual tablets, each containing a desired dose of Amino AcidCompound. The separating process may be accomplished when the Amino AcidCompound is in a solid, liquid, or semisolid state.

Those of ordinary skill in the art will be able to readily selectmanufacturing equipment and pharmaceutically acceptable additives orinert ingredients to manufacture implementations of an Amino AcidCompound. For the exemplary purposes of this disclosure, some examplesof pharmaceutically acceptable additives or inert ingredients andmanufacturing process are included below, particularly those that relateto manufacture of implementations of an Amino Acid Compound in tabletform. Notwithstanding the specific examples given, it will be understoodthat those of ordinary skill in the art will readily appreciate how tomanufacture implementations of an Amino Acid Compound according to theother methods of administration and delivery disclosed in this document.

A particular implementation of an Amino Acid Compound may include alubricant. Lubricants are any anti-sticking agents, glidants, flowpromoters, and the like materials that perform a number of functions intablet manufacture, for example, such as improving the rate of flow ofthe tablet granulation, preventing adhesion of the tablet material tothe surface of the dies and punches, reducing interparticle friction,and facilitating the ejection of the tablets from the die cavity.Lubricants may comprise, for example, magnesium stearate, calciumstearate, talc, and colloidal silica.

Particular implementations of an Amino Acid Compound may also include abinder. Binders are any agents used to impart cohesive qualities topowdered material through particle-particle bonding. Binders mayinclude, for example, matrix binders (e.g. dry starch, dry sugars), filmbinders (e.g. celluloses, bentonite, sucrose), and chemical binders(e.g. polymeric cellulose derivatives, such as methyl cellulose, carboxymethyl cellulose, and hydroxy propyl cellulose); and other sugar,gelatin, non-cellulosic binders and the like.

Disintegrators may be used in particular implementations of an AminoAcid Compound to facilitate the breakup or disintegration of tabletsafter administration. Disintegrators may include, for example, starch,starch derivatives, clays (e.g. bentonite), algins, gums (e.g. guargum), cellulose, cellulose derivatives (e.g. methyl cellulose,carboxymethyl cellulose), croscarmellose sodium, croscarmellosecellulose, and other organic and inorganic materials.

Implementations of an Amino Acid Compound may include diluents, or anyinert substances added to increase the bulk of the Amino Acid Compoundto make a tablet a practical size for compression. Diluents may include,for example, calcium phosphate, calcium sulfate, lactose, mannitol,magnesium stearate, potassium chloride, and citric acid, among otherorganic and inorganic materials.

Buffering agents may be included in an Amino Acid Compound and may beany one of an acid and a base, where the acid is, for example, propionicacid, p-toluenesulfonic acid, salicylic acid, stearic acid, succinicacid, tannic acid, tartaric acid, thioglycolic acid, or toluenesulfonicacid, and the base is, for example, ammonium hydroxide, potassiumhydroxide, sodium hydroxide, sodium hydrogen carbonate, aluminumhydroxide, calcium carbonate, and other organic and inorganic chemicals.

Implementations of an Amino Acid Compound may also be administeredthrough use of amphipathic lipid delivery systems (such as liposomes andunilamellar vesicles), caplet systems, oral liquid systems, parenteraland/or intravenous systems, topical systems (creams, gels, transdermalpatches, etc.), intranasal systems, rectal or vaginal systems, and manyother delivery methods and/or systems known to those of ordinary skillin the art. Those of ordinary skill in the art will readily be able toselect additional pharmaceutically acceptable additives to enabledelivery of implementations of a pharmaceutical composition from thedisclosure in this document.

With respect to delivery of particular implementations of an Amino AcidCompound, for the exemplary purposes of this disclosure, tablets may beutilized. Tablets are any solid pharmaceutical dosage form containing apharmaceutically acceptable active agent or agents to be administeredwith or without suitable pharmaceutically acceptable additives andprepared either by compression or molding methods well known in the art.Tablets have been in widespread use and remain popular as a dosage formbecause of the advantages afforded both to the manufacturer (e.g.,simplicity and economy of preparation, stability, and convenience inpackaging, shipping, and dispensing) and the patient (e.g., accuracy ofdosage, compactness, portability, blandness of taste, and ease ofadministration). Although tablets are most frequently discoid in shape,they may also be round, oval, oblong, cylindrical, rectangular ortriangular, for example. The tablets may be optionally scored so thatthey may be separated into different dosages. They may differ greatly insize and weight depending on the amount of the pharmaceuticallyacceptable active agent or agents present and the intended route ofadministration. They are divided into two general classes, (1)compressed tablets, and (2) molded tablets.

Tablets and other orally discrete dosage forms, such as capsules,cachets, pills, granules, pellets, beads, and particles, for example,may optionally be coated with one or more enteric coatings, sealcoatings, film coatings, barrier coatings, compress coatings, fastdisintegrating coatings, or enzyme degradable coatings for example.Multiple coatings may be applied for desired performance. Further,dosage forms may be designed for, by non-limiting example, immediaterelease, pulsatile release, controlled release, extended release,delayed release, targeted release, synchronized release, or targeteddelayed release. For release/absorption control, carriers may be made ofvarious component types and levels or thicknesses of coats. Such diversecarriers may be blended in a dosage form to achieve a desiredperformance. In addition, the dosage form release profile may beeffected by a polymeric matrix composition, a coated matrix composition,a multi-particulate composition, a coated multi-particulate composition,an ion-exchange resin-based composition, an osmosis-based composition,or a biodegradable polymeric composition.

While manufacture of implementations of an Amino Acid Compound have beendescribed in particular sequences of steps and/or in particular forms,it will be understood that such manufacture is not limited to thespecific order of steps or forms as disclosed. Any steps or sequences ofsteps of manufacture of implementations of an Amino Acid Compound in anyform are given as examples of possible steps or sequences of steps orpotential forms and not as limitations, since many possiblemanufacturing processes and sequences of steps may be used tomanufacture Amino Acid Compound implementations in a wide variety offorms.

Use

Implementations of an Amino Acid Compound are particularly useful inincreasing vasodilation in humans and animals. However, implementationsare not limited to uses relating to vasodilation modification, and thelike. Rather, any description relating to the foregoing is for theexemplary purposes of this disclosure. It will be understood thatimplementations of an Amino Acid Compound may encompass a variety ofuses and are not limited in their uses. For example, possible uses maybe, by non-limiting example, prevention of Nitrate tolerance, enhancedwater solubility, increased distribution to muscles, and/or counteringNitric Oxide inhibiting effects of certain Amino Acids.

In conventional preparations of Nitrate compounds, “tolerance,” aparticular side effect, has been observed in many patients. This isunfortunate because the effectiveness of Nitrate on vasodilation is welldocumented. “Tolerance” occurs when a subject's reaction to Nitratedecreases so that larger doses are required to achieve the same effect.A Mar. 3, 2000 report in the British Journal of Pharmacology indicatesthat “tolerance to the dilator effects of nitrates remains a persistingtherapeutic problem.” Raymond J. MacAllister “Arginine and NitrateTolerance” available athttp://www.nature.com/bjp/journal/v130/n2/full/0703340a.html, thecontents of which are hereby incorporated herein by reference.

Empirical studies indicate that Nitrates are useful for theirvasolidating effects. Common Nitrates include nitroglycerin andisosorbide dinitrate. Nitrates exert their vasodilating effect throughtheir reduction to Nitrites. In vivo, Nitrates are reduced to Nitritesand, in the blood vessels' epithelial cells, Nitrite reacts with a thioldonor (mainly glutathione) to yield Nitric Oxide. Louis J. Ignarro,“After 130 years, the Molecular Mechanism of Action of Nitroglycerin isRevealed” (Jun. 11, 2002) available athttp://www.pnas.org/cgi/content/full/99/12/7816?ck=nck, the contents ofwhich are hereby incorporated herein by reference.

The Nitric Oxide inhibiting characteristics of the Amino Acid Glutaminehave been well documented in a number of studies. In particular, a Mar.28, 2006 report in the American Journal of Physiology has found thatGlutamine inhibits Nitric Oxide production by downregulation of eNOSsynthase. Masao Kakoki, et al. “Amino acids as Modulators ofEndothelium-Derived Nitric Oxide.” available athttp://ajprenal.physiology.org/cgi/content/full/291/2/F297, the contentsof which are hereby incorporated by reference.

A January 2006 Journal of Nutrition report indicates that the Amino AcidLeucine promotes anabolism and stimulates muscle protein synthesis.Michael J. Rennie, et al. “Branched-Chain Amino Acids as Fuels andAnabolic Signals in Human Muscle” available athttp://jn.nutrition.org/cgi/content/full/136/1/264S, the contents ofwhich are hereby incorporated by reference.

Empirical studies indicate that the Amino Acid Norvaline inhibits theenzyme arginase and thus decreases the rate of conversion of the AminoAcid Arginine to urea. Takeyori Saheki, et al. “Regulation of UreaSynthesis in Rat Liver” available athttp://jb.oxfordjournals.org/cgi/content/abstract/86/3/745?ijkey=5d134456b7443ca36c809269462276e532549798&keytype2=tf_ipsecsha,the contents of which are hereby incorporated by reference.

An October 2004 Journal of Nutrition report indicates that the AminoAcid Ornithine promotes anabolism and stimulates muscle proteinsynthesis. Michael J. Rennie, et al. “Branched-Chain Amino Acids asFuels and Anabolic Signals in Human Muscle” available athttp://jn.nutrition.org/cgi/content/full/136/1/264S, the contents ofwhich are hereby incorporated by reference.

Empirical studies indicate that the Amino Acids Beta-Beta Alanine andL-Histidine support carnosine production. M. Dunnett, “Influence of OralBeta-Beta Alanine and L-Histidine Supplementation on the CarnosineContent of the Gluteus Medius” Equine Veterinary Journal Supplement,available athttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=ShowDetailView&TermToSearch=10659307&ordinalpos=4&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed,the contents of which are hereby incorporated by reference.

Empirical studies further indicate that the Amino Acids Beta Alanine andL-Histidine increase muscle power, recuperation and stamina. YoshihiroSuzuki “High Level of Skeletal Muscle Carnosine Contributes to theLatter Half of Exercise Performance During 30-S Maximal Cycle ErgometerSprinting” in the Japanese Journal of Physiology, available athttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=ShowDetailView&TermToSearch=12139778&ordinalpos=4&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum,the contents of which are hereby incorporated by reference.

Accordingly, Applicants have discovered that the Arginine compoundaccording to the first implementation, when ingested, provides enhancedNitric Oxide (NO—) production while providing improved vasodilationeffects over single administration of Arginine, the singleadministration of Nitrates, or the single administration of Nitrites.Improved vasodilation may, in turn, provide better circulation anddistribution of Arginine in the body. Absorption may be improved sinceAmino Acid salts with inorganic acids are much more water soluble thansingle administration Amino Acids. Applicants have also discovered thatthe vasodilating effect of Arginine Nitrate manifests faster than thatof single-administration Arginine, and as fast as any nitrate, since theNO₃— group of the salt requires minimal conversion to yield NitricOxide. Additionally a much lesser dose may be required for vasodilationto take place, compared to the single administration of Arginine.Likewise, the development of tolerance to the nitrate component of themolecule may be prevented with the presence of Arginine. ArginineNitrate may promote vasodilation through production of Nitric Oxide bytwo different pathways, the Arginine citrullization pathway and thenitrate reduction pathway. Arginine Nitrate may likewise be more watersoluble than single administration Arginine.

Accordingly, Applicants have discovered that the Citrulline compoundaccording to the second implementation, when ingested, provides enhancedNitric Oxide (NO—) production while providing improved vasodilationeffects over single administration of Citrulline, the singleadministration of Nitrates, or the single administration of Nitrites.Improved vasodilation may, in turn, provide better circulation anddistribution of Citrulline in the body. Absorption may be improved sinceAmino Acid salts with inorganic acids are much more water soluble thansingle administration Amino Acids. Additionally a much lesser dose maybe required for vasodilation to take place, compared to the singleadministration of Citrulline or nitrates. Citrulline Nitrate is likewisemore water soluble than single administration Citrulline.

Accordingly, Applicants have discovered that the Creatine compoundaccording to the third implementation, when ingested, provides enhancedNitric Oxide (NO—) production while providing improved vasodilationeffects over single administration of Creatine, the singleadministration of Nitrates, or the single administration of Nitrites.Improved vasodilation may, in turn, provide better circulation anddistribution of Creatine in the body. Absorption may be improved sinceAmino Acid salts with inorganic acids are much more water soluble thansingle administration Amino Acids. Additionally a much lesser dose maybe required for vasodilation to take place, compared to the singleadministration of nitrates. Creatine Nitrate is likewise more watersoluble than single administration Creatine.

Accordingly, Applicants have discovered that the Glutamine compoundaccording to the fourth implementation, when ingested, counters theNitric Oxide (NO—) inhibiting characteristics of Glutamine. Absorptionof Glutamine may be improved since Amino Acid salts with inorganic acidsare much more water soluble than single administration Amino Acids.Additionally a much lesser dose may be required for vasodilation to takeplace, compared to the single administration of nitrates. GlutamineNitrate may likewise be more water soluble than single administrationGlutamine.

Accordingly, Applicants have discovered that the Leucine compoundaccording to the fifth implementation, when ingested, provides enhancedNitric Oxide (NO—) production while providing improved vasodilationeffects over single administration of Leucine, the single administrationof Nitrates, or the single administration of Nitrites. Improvedvasodilation may, in turn, provide better circulation and distributionof Leucine in the body. Absorption may be improved since Amino Acidsalts with inorganic acids are much more water soluble than singleadministration Amino Acids. Additionally a much lesser dose may berequired for vasodilation to take place, compared to the singleadministration of nitrates. Leucine Nitrate is likewise more watersoluble than single administration Leucine.

Accordingly, Applicants have discovered that the Norvaline compoundaccording to the sixth implementation, when ingested, promotesvasodilation through the inhibition of arginase, while promoting NitricOxide formation via the nitrate mechanism. Improved vasodilation may, inturn, provide better circulation and distribution of Norvaline in thebody. Absorption may be improved since Amino Acid salts with inorganicacids are much more water soluble than single administration AminoAcids. Additionally a much lesser dose may be required for vasodilationto take place, compared to the single administration of nitrates.Norvaline Nitrate may likewise be more water soluble than singleadministration Norvaline.

Accordingly, Applicants have discovered that the Ornithine compoundaccording to the seventh implementation, when ingested, provides anadditional vasodilation mechanism, reducing the amount of Ornithineneeded and the amount of time needed for the vasodilating properties tomanifest. Improved vasodilation may, in turn, provide better circulationand distribution of Ornithine in the body. Absorption may be improvedsince Amino Acid salts with inorganic acids are much more water solublethan single administration Amino Acids. Applicants have also discoveredthat Ornithine Nitrate begins acting as fast as any other nitrate, sincethe NO₃— group of the salt requires minimal conversion to yield NitricOxide. Additionally, a much lesser dose may be required for vasodilationto take place, compared to the single administration of nitrates.Ornithine Nitrate may likewise be more water soluble than singleadministration Ornithine.

Accordingly, Applicants have discovered that the Histidine compoundaccording to the eighth implementation, when ingested, provides avasodilation mechanism. Vasodilation may, in turn, provide bettercirculation and distribution of Histidine in the body. Applicants havelikewise discovered that the Histidine compound according to the ninthimplementation, when ingested, promotes carnosine production, thusincreasing muscle power, endurance and recuperation. Absorption may beimproved since Amino Acid salts with inorganic acids are much more watersoluble than single administration Amino Acids. Applicants have alsodiscovered that Histidine Nitrate begins acting as fast as any othernitrate, since the NO₃— group of the salt requires minimal conversion toyield Nitric Oxide. Additionally, a much lesser dose may be required forvasodilation to take place, compared to the single administration ofnitrates. Histidine Nitrate may likewise be more water soluble thansingle administration Histidine.

Accordingly, Applicants have discovered that the Beta Alanine compoundaccording to the ninth implementation, when ingested, providesvasodilation. Vasodilation may, in turn, provide better circulation anddistribution of Beta Alanine in the body. Applicants have likewisediscovered that the Beta Alanine compound according to the tenthimplementation, when ingested, promotes carnosine production, thusincreasing muscle power, endurance and recuperation. Absorption may beimproved since Amino Acid salts with inorganic acids are much more watersoluble than single administration Amino Acids. Applicants have alsodiscovered that Beta Alanine Nitrate begins acting as fast as any othernitrate, since the NO₃— group of the salt requires minimal conversion toyield Nitric Oxide. Additionally, a much lesser dose may be required forvasodilation to take place, compared to the single administration ofnitrates. Beta Alanine Nitrate may likewise be more water soluble thansingle administration Beta Alanine.

Accordingly, Applicants have discovered that the Agmatine compoundaccording to the eighth implementation, when ingested, counteracts theNitric Oxide inhibiting effect of single administration Agmatine.Absorption may be improved since Amino Acid salts with inorganic acidsare much more water soluble than single administration Amino Acids.Applicants have also discovered that Agmatine Nitrate begins acting asfast as any other nitrate, since the NO₃— group of the salt requiresminimal conversion to yield Nitric Oxide. Agmatine Nitrate may likewisebe more water soluble than single administration Agmatine.

1. A method for increasing the bioabsorption of amino acids in a humanor animal, the method comprising administering to the human or animal apharmaceutically effective amount of an amino acid compound consistingessentially of a nitrate or nitrite of an amino acid selected from thegroup consisting of Arginine, Agmatine, Beta Alanine, Citrulline,Creatine, Glutamine, L-Histidine, Isoleucine, Leucine, Norvaline,Ornithine, and Valine.